1974-1975 Fellow, Foundations Fund for Research in Psychiatry1980-1982 Fellow in Neuroscience, Alfred N. Sloan Foundation2005 Elected Fellow, American Association for the Advancement of Science

ResearchAbstract

Our research centers on the capacity for reorganization in the central nervous system. Animals that sustain sudden injury to particular brain pathways can exhibit remarkable improvement in sensory and motor functions. Although the models of strutural and chemical reorganization in the brain-damaged animals provided new insight into the remarkable diversity of neuronal mechanisms that permit restoration of function, human neurodegenerative disorders (especially those associated with aging-such as Parkinson's and Alzheimer's diseases) are insidious in onset. Two major forefronts of research are to identify the processes that dispose certain neurons to degenerate in these diseases, and to determine means by which the brain's compensatory mechanisms may be induced to retard slow degenerative processes or to counteract their function consequences.

These considerations have prompted an analysis of patterns of brain dopaminergic innervation of the basal ganglia and studies of the distribution of the major subtypes of dopamine receptor (D-1 and D-2) in this motor area. In particular, using quantitative autoradiographic markers for the dopamine nerve terminals as well as for the D-1 and D-2 receptors, a complete picture has emerged of the organization of dopaminergic synapses in this structure. Important new information has emerged from our research concerning how this synaptic neurochemistry reorganizes itself in rodent and nonhuman primate models of Parkinson's disease. Similar analyses have been performed on postmortem human basal ganglia tissue, and experiments are planned to extend these studies to postmortem tissue derived from patients with diagnosed Parkinsonism.

Our research also is actively investigating factors responsible for the neurodegeneration occurring in Parkinsonism by using animals that undergo injury to the nigrostriatal dopamine projection as a consequence of exposure to neurotoxic agents (6-hydroxydopamine, MPTP, methamphetamine) or as a mutation ("weaver" mouse). Just as in Parkinson's disease, rodents undergoing degeneration to this pathway show considerable heterogeneity in their pathology, with certain dopamine-containing neurons being more vulnerable than others to injury. Cellular markers that distinguish vulnerable from resistant neurons have been identified.